In contrast to the overwhelming success of radiolabeled antibodies in treating hematologic malignancies, only modest success has been achieved in the radioimmunotherapy of solid tumors. One of the limitations in successful application of radioimmunotherapy is the large molecular size of the intact immunoglobulin that results in prolonged serum half-life and poor tumor penetration and uptake. With the advent of antibody engineering, small molecular weight antibody fragments exhibiting improved pharmacokinetics and tumor penetration have been generated. However, their clinical application has been limited by suboptimal tumor uptake and short tumor residence time. Optimization of the molecular size of the antibodies alone is therefore not sufficient for clinical success of radioimmunotherapy.
Indeed, apart from their large size, radiolabeled antibodies encounter other impediments before reaching their target antigens expressed on the cell surface of solid tumors. Some of these barriers include poor blood flow in large tumors, permeability of vascular endothelium, elevated interstitial fluid pressure of tumor stroma, and heterogeneous antigen expression.
New optimization strategies involve the use of biological modifiers to modulate the impediments posed by solid tumors. In combination with radiolabeled antibodies, various agents are being used to improve the tumor blood flow, enhance vascular permeability, lower tumor interstitial fluid pressure by modulating stromal cells and extracellular matrix components, up-regulate the expression of target antigens, and improve the penetration and retention of the radiopharmaceuticals.
Nevertheless, the clinical success of radioimmunotherapy for solid tumors still seems to be a distant dream because only a very small amount of administered antibody (as low as 0.001-0.01%) localizes in the tumor and administration of higher amounts of radiolabeled mAbs causes myelotoxicity. To be clinically successful, radioimmunotherapy for solid tumors needs to be optimized so as to enhance the tumor uptake and retention of radiolabeled antibodies in the tumor and minimizing the exposure of non-target tissues.
Pruszynski et al. (2014) showed improved tumor targeting of a HER2-targeting VHH through labeling with 131I using N-succinimidyl-4-guanidinomethyl 3-125-131I-iodobenzoate, when compared to radioiodination with Nε-(3-*I-iodobenzoyl)-Lys5-Nα-maleimido-Gly1-GEEEK and direct radioiodination of the VHH using IODO-GEN. Tumor uptake for the *I-SGMIB-VHH was significantly reduced with Trastuzumab blocking, indicating competition between the VHH and Trastuzumab for HER2 binding. The VHH disclosed in Pruszynski et al. contains a carboxy-terminal cysteine-containing tail, resulting in an equilibrium mixture of monomeric and dimeric forms. Pruszynski et al. failed to show any therapeutic effect of the radiolabeled VHHs.